CA2602281C - Gynecological drugs encapsulated in sodium alginate microspheres for use in embolotherapy - Google Patents
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Abstract
The present invention relates to a kind of sodium alginate microsphere vascular embolus containing gynecological drug and its preparation. The preparation of it consists of the following steps: preparing the solution of gynecological drug, sodium alginate and dilvalent metal cations such as BaCl2 , Mg Cl2 or CaCl2 etc. by order; mixing the gynecological drug solution and sodium alginate solution, and then mixing them with the curing solution of BaCl2 or CaCl2 and the like. Then the obtained is the sodium alginate microshere vascular embolus containing gynecological drug. The carrier materials of the vascular embolus according to the invention are natural extracts and have good biocompatibility and re biodegradable; the side effect of the pharmaceutic loaded by them is minimal, and it is especially suitable for myometrial gland and hysteromyoma.
Description
Gynecological Drugs Encapsulated In Sodium Alginate Microspheres For Use In Embolotherapy Field of the Invention The present invention relates to a kind of sodium alginate microsphere vascular embolus containing gynecological drug and its preparation.
Background of the Invention Uterine fibroids and adenomyosis are the common benign disorders of female reproductive system. The high morbidity of these disorders definitely influences the quality of life of women. Medication and operation are the main therapeutic options at present. Hysterectomy is the main operation method, which is required for those with severe symptoms and elders without demand of pregnancy. Medication is suitable for the youngers with desire of pregnency, people with mild symptoms or near menopause, including Danazol, gonadotropin releasing hormone analogues (GnRHa), Mifepristone (Ru486), androgen, gestrinone, etc.
Danazol is an artificially synthesized derivative of 17-acetylene testosterone with mild androgen-like function. In vitro study has confirmed that Danazol may directly act at: (1) the hypothalamus-pituitary-ovary axis and inhibit the release of gonadotropin-releasing hormone, (2) ovary and inhibit the synthesis of ovarian hormones, (3) uterine membrane and result in atrophy of the membrane and pseudo-menopause, and (4) ectopic membrane and reduce the expression of cytochrome P450 (an aroma enzyme). However, side-effects as hepatotoxicity of Danazol limit its long-term application in clinical practice.
Gonadotropin releasing hormone analogues (GnRHa) is a kind of artificially synthesized deca-peptide compound, which can decrease the secretion of gonadotropin and ovarian hormones by means of depressing GnRHa receptor in pituitary gland, leading to atrophy of uterine membrane. Lower estrogen concentration caused by GnRHa may reduce the arterial blood supply of uterus by decreasing the vessel lumen, then reduce the size of fibroids ulteriorly. GnRHa also possesses direct action on uterine membrane.
GnRHa may lead to artificial menopause so as to relieve the symptoms caused by adenomyosis, and markedly reduce the size of uterus and increase the possibility of pregnancy. GnRHa can prohibit the growth of fibroids, and pre-operative application (i.e., 3-6 months earlier) could reduce intraoperative bleeding. The main side-effect of GnRHa is menopause symptoms and osteoporosis caused by lower sex hormones, and GnRHa lacks of long-term efficacy.Higher rate of recurrence happens when GnRHa is ceased.
Androgen, Gestrinone, and Mifepristone(Ru486) act on hypothalamus-pituitary-ovary axis by means of non-rivalrous anti-estrogen, resulting in suspension of ovulation, decrease of progestogen level, decrease of arterial blood supply of uterus and atrophy of fibroids. Gestrinone is the derivative of methyltestosterone, and the mechanism is similar to that of Danazol. The side-effects as hepatotoxicity of the drugs mentioned above limit their extensive application in routine clinical practice.
With its rapid development, interventional radiology has playing an important role in modern medicine. As a result, an additional option is available for the patients with fibroids and adenomyosis besides hysterectomy and medication: interventional microinvasive therapy.
The characteristics and advantages of interventional transarterial embolotherapy for the treatment of fibroids and adenomyosis include:
1.Replacing open surgery by minimally invasive technique may relieve the patients not only physically but also psychologically;
Background of the Invention Uterine fibroids and adenomyosis are the common benign disorders of female reproductive system. The high morbidity of these disorders definitely influences the quality of life of women. Medication and operation are the main therapeutic options at present. Hysterectomy is the main operation method, which is required for those with severe symptoms and elders without demand of pregnancy. Medication is suitable for the youngers with desire of pregnency, people with mild symptoms or near menopause, including Danazol, gonadotropin releasing hormone analogues (GnRHa), Mifepristone (Ru486), androgen, gestrinone, etc.
Danazol is an artificially synthesized derivative of 17-acetylene testosterone with mild androgen-like function. In vitro study has confirmed that Danazol may directly act at: (1) the hypothalamus-pituitary-ovary axis and inhibit the release of gonadotropin-releasing hormone, (2) ovary and inhibit the synthesis of ovarian hormones, (3) uterine membrane and result in atrophy of the membrane and pseudo-menopause, and (4) ectopic membrane and reduce the expression of cytochrome P450 (an aroma enzyme). However, side-effects as hepatotoxicity of Danazol limit its long-term application in clinical practice.
Gonadotropin releasing hormone analogues (GnRHa) is a kind of artificially synthesized deca-peptide compound, which can decrease the secretion of gonadotropin and ovarian hormones by means of depressing GnRHa receptor in pituitary gland, leading to atrophy of uterine membrane. Lower estrogen concentration caused by GnRHa may reduce the arterial blood supply of uterus by decreasing the vessel lumen, then reduce the size of fibroids ulteriorly. GnRHa also possesses direct action on uterine membrane.
GnRHa may lead to artificial menopause so as to relieve the symptoms caused by adenomyosis, and markedly reduce the size of uterus and increase the possibility of pregnancy. GnRHa can prohibit the growth of fibroids, and pre-operative application (i.e., 3-6 months earlier) could reduce intraoperative bleeding. The main side-effect of GnRHa is menopause symptoms and osteoporosis caused by lower sex hormones, and GnRHa lacks of long-term efficacy.Higher rate of recurrence happens when GnRHa is ceased.
Androgen, Gestrinone, and Mifepristone(Ru486) act on hypothalamus-pituitary-ovary axis by means of non-rivalrous anti-estrogen, resulting in suspension of ovulation, decrease of progestogen level, decrease of arterial blood supply of uterus and atrophy of fibroids. Gestrinone is the derivative of methyltestosterone, and the mechanism is similar to that of Danazol. The side-effects as hepatotoxicity of the drugs mentioned above limit their extensive application in routine clinical practice.
With its rapid development, interventional radiology has playing an important role in modern medicine. As a result, an additional option is available for the patients with fibroids and adenomyosis besides hysterectomy and medication: interventional microinvasive therapy.
The characteristics and advantages of interventional transarterial embolotherapy for the treatment of fibroids and adenomyosis include:
1.Replacing open surgery by minimally invasive technique may relieve the patients not only physically but also psychologically;
2.Replacing whole body medication by regional embolotherapy with embolic agent/combined with infusion/biologically degradable embolic agent may:
Increase drug concentration in the target region;
Decrease side-effects and toxicity caused by medication;
Provide double effects caused by embolization and regional drug-release;
(A)Possible pregnancy due to preservation of uterus.
Increase drug concentration in the target region;
Decrease side-effects and toxicity caused by medication;
Provide double effects caused by embolization and regional drug-release;
(A)Possible pregnancy due to preservation of uterus.
3.Decrease side-effects resulted from open surgery;
4.Decrease financial burden because of shortening of hospitalization due to minimally invasive technique;
5.Increase both the social and economic benefits.
Particularly, the ages of patients suffering fibroids tend to become more and more smaller, and hysterectomy or medication is hard to satisfy the demand of preservation of uterus/ability of pregnancy.
The rapidly developed techniques of interventional therapy provide optional treatment in the field of gynecology and obstetrics. Interventional therapy is defined as superselective intraarterial infusion of embolic agent into the target region under radiological guidance such as DSA, leading to therapeutic efficacy charactered by atrophy/necrosis of the fibroids or target lesion. Among the interventional therapies for fibroids and adenomyosis, embolization of uterine artery (UAE) is the most rapidly developed one. Since 1979, UAE is widely used for the treatment of vital postpartum bleeding, ectopic pregnancy and post-operative hemorrhage, as well as malignant tumors in recent years.UAE
has been proved to be safe and effective by numerous researches/publications during clinical practice of more than twenty years without ischemic necrosis of the target organ.
UAE for the treatment of fibroids and adenomyosis is used in clinical practice world-widely at present. UAE can cause regional ischemia of uterus and desquamation of uterine-membrane, which leads to the relief of the symptoms and improvement of the quality of life. 37^-85% shrinkage of fibroids is also reported, which results in improvement of symptoms in 95% of the patients.
In selected patients, UAE could replace medication/hysterectomy in the patients who are aimed in relief of symptoms caused by benign tumors as fibroids.
Simple embolization with embolic agent can interrupt the blood supply of the target region (tumor), which leads to therapeutic efficacy represented by atrophy and necrosis.
Disadvantages of regional drug infusion include: uneven release of the drug and necrosis/injury of tissue caused by highly concentrated drug.
At present there is no precedent at home and abroad to take sodium alginate as drug carrier to wrap gynecological drug, and apply it in gynecological patients by vascular embolotherapy.
Summary of the Invention In one particular embodiment there is provided sodium alginate microspheres containing a gynecological drug, wherein the microspheres comprise sodium alginate as a carrier, and the gynecological drug is enwrapped by the sodium alginate, and wherein the microspheres form a vascular embolus in a vein upon administration to a patient.
One objective of the present invention is to provide a kind of sodium alginate microsphere vascular embolus containing gynecological drug, which has good biological tolerance, less side-effects, therapeutic efficacy of embolization and medication at the same time and releases uniformly, which results in improved efficacy in treating fibroids and adenomyosis.
The said objective of the present invention is achieved by the following technique protocol.
A kind of sodium alginate microsphere vascular embolus containing gynecological drug, which is composed of sodium alginate as a drug carrier and gynecological drug which is encapsulated by said sodium alginate.
The weight ratio of said sodium alginate and said gynecological drug ranges from 1:1 to 90:1.
The said gynecological drugs include: Danazol, gonadotropin releasing hormone analogues (GnRHa), Mifepristone, Gestrinone or androgen.
The said sodium alginate microsphere vascular embolus containing gynecological drug may be microgel particles or microspheres reserving in curing solution.
The said sodium alginate microsphere vascular embolus containing gynecological drug may also be powdery granule.
4a The diameter of the said microgel particles or microspheres reserving in the curing solution ranges from 200^550 m, 400^750 m, or 600^950 m.
The diameter of the said powdery granule ranges from 100^-350 m, 200-550 m or 400^-750 m.
Another objective of the present invention is to provide preparation of sodium alginate microshere vascular embolus containing gynecological drug mentioned above.
The said objective of the present invention is achieved by the following technique protocol.
The preparation of sodium alginate microshere vascular embolus containing gynecological drug consists of the following steps:
1. Gynecological drug solution is prepared by dissolving a certain rate of gynecological drug with solvent;
2. Sodium alginate solution is prepared by dissolving a certain rate of sodium alginate;
3. Curing solution is prepared by dissolving calcium chloride, barium chloride or magnesium chloride with the concentration of 1-10%;
4. Gynecological drug solution is mixed with sodium alginate solution, then the mixture is added dropwise to curing solution under a high-voltage electrostatic droplets device to form sodium alginate microspheres or microgel particles containing gynecological drug.
The high-voltage electrostatic droplets device comprises an electrostatic device, said electrostatic device has positive and negative electrodes. The positive electrode is connected with a needle of a micro-syringe device and the negative electrode is connected with a stainless steel wires emerged in the bivalent metal cationic curing solution. The mixture solution of gynecological drug and sodium alginate in the micro-syringe device is dripped into the bivalent cationic curing solution to form microspheres.
The obtained sodium alginate microshere vascular embolus containing gynecological drug is the microsphere reserving in the curing solution, which is called as wet-microsphere, the diameter can range from 200---550 m, 400^-750 m or 600950 m. Wet-microsphere of 300^-550 m is required for the treatment of adenomyosis, 500^750 m for uterine fibroids, and 700^950 m for the patients with demand of pregnancy.
The obtained sodium alginate microshere vascular embolus containing gynecological drug is decanted, then the lower microgel particles are put into the oven and kept in a sealed condition. The obtained powdery granules are called dry microspheres. The diameters of which may range from 100^-350 m, 200550 m or 400^750 m. Dry microsphere of 100^-350 m is required for the treatment of adenomyosis, 200^550 m for uterine fibroids, and 400--750 m for the patients with demand of pregnancy.
The third objective of the present invention is to provide application of the sodium alginate microshere vascular embolus containing gynecological drug mentioned above.
The said objective of the present invention is achieved by the following technique protocol.
By adopting intervention radiotherapy or intervention ultrasound, the duct is inserted into feeding artery of target organ to conduct arteriography. The selected diameter of embolus microsphere is determined according to the impression of arteriography. Aseptically open the bottle and leave it until the microspheres are settled at the bottom of the bottle. Remove the curing solution by a syringe then add an equal amount of normal saline to wash the microspheres three times, or remove the curing solution by a syringe then add an equal amount of normal saline, pour normal saline and microsphere into an aseptic bowl. Rinse the microsphere using 50-60 mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e.
embolism is finished. Arteriography is conducted again to judge the effect of embolism.
If the sodium alginate microshere vascular embolus containing gynecological drug is powdery granule, then the dry microsphere reserving in sealed container are dissolved in normal saline to swell (wet microsphere), then appropriate amount or diluted contrast medium is added to mix evenly (leaving microsphere thoroughly floating in the contrast medium), and then the mixture is infused slowly or slowly in multiple times in the vessel of the affected portion to embolism ultraselectively by duct under the monitor of image documentation equipment (Over-embolization is absolutely prohibited.) till the flow rate of contrast medium is obviously reduced, i.e. embolism is finished. Arteriography is conducted again to judge the effect of embolism.
The following is the further illustration of the present invention in embodiments, but it does not mean any limitation for the protection range of it.
Detailed Description of the Invention Example 1 Preparation of sodium alginate microsphere vascular embolus containing Danazol 1. Preparation before wrapping Disposal of glass utensil:
The clean glass utensil is dried then kept in oven at 300 C for 3 hours (the heat source is removed till the bacteria are killed);
(2) Preparation of Danazol solution:
1.5 kg Danazol available in market is weighed and placed in the glass utensil mentioned above, propylene glycol is added dropwise till Danazol is completely dissolved to make a Danazol solution;
Particularly, the ages of patients suffering fibroids tend to become more and more smaller, and hysterectomy or medication is hard to satisfy the demand of preservation of uterus/ability of pregnancy.
The rapidly developed techniques of interventional therapy provide optional treatment in the field of gynecology and obstetrics. Interventional therapy is defined as superselective intraarterial infusion of embolic agent into the target region under radiological guidance such as DSA, leading to therapeutic efficacy charactered by atrophy/necrosis of the fibroids or target lesion. Among the interventional therapies for fibroids and adenomyosis, embolization of uterine artery (UAE) is the most rapidly developed one. Since 1979, UAE is widely used for the treatment of vital postpartum bleeding, ectopic pregnancy and post-operative hemorrhage, as well as malignant tumors in recent years.UAE
has been proved to be safe and effective by numerous researches/publications during clinical practice of more than twenty years without ischemic necrosis of the target organ.
UAE for the treatment of fibroids and adenomyosis is used in clinical practice world-widely at present. UAE can cause regional ischemia of uterus and desquamation of uterine-membrane, which leads to the relief of the symptoms and improvement of the quality of life. 37^-85% shrinkage of fibroids is also reported, which results in improvement of symptoms in 95% of the patients.
In selected patients, UAE could replace medication/hysterectomy in the patients who are aimed in relief of symptoms caused by benign tumors as fibroids.
Simple embolization with embolic agent can interrupt the blood supply of the target region (tumor), which leads to therapeutic efficacy represented by atrophy and necrosis.
Disadvantages of regional drug infusion include: uneven release of the drug and necrosis/injury of tissue caused by highly concentrated drug.
At present there is no precedent at home and abroad to take sodium alginate as drug carrier to wrap gynecological drug, and apply it in gynecological patients by vascular embolotherapy.
Summary of the Invention In one particular embodiment there is provided sodium alginate microspheres containing a gynecological drug, wherein the microspheres comprise sodium alginate as a carrier, and the gynecological drug is enwrapped by the sodium alginate, and wherein the microspheres form a vascular embolus in a vein upon administration to a patient.
One objective of the present invention is to provide a kind of sodium alginate microsphere vascular embolus containing gynecological drug, which has good biological tolerance, less side-effects, therapeutic efficacy of embolization and medication at the same time and releases uniformly, which results in improved efficacy in treating fibroids and adenomyosis.
The said objective of the present invention is achieved by the following technique protocol.
A kind of sodium alginate microsphere vascular embolus containing gynecological drug, which is composed of sodium alginate as a drug carrier and gynecological drug which is encapsulated by said sodium alginate.
The weight ratio of said sodium alginate and said gynecological drug ranges from 1:1 to 90:1.
The said gynecological drugs include: Danazol, gonadotropin releasing hormone analogues (GnRHa), Mifepristone, Gestrinone or androgen.
The said sodium alginate microsphere vascular embolus containing gynecological drug may be microgel particles or microspheres reserving in curing solution.
The said sodium alginate microsphere vascular embolus containing gynecological drug may also be powdery granule.
4a The diameter of the said microgel particles or microspheres reserving in the curing solution ranges from 200^550 m, 400^750 m, or 600^950 m.
The diameter of the said powdery granule ranges from 100^-350 m, 200-550 m or 400^-750 m.
Another objective of the present invention is to provide preparation of sodium alginate microshere vascular embolus containing gynecological drug mentioned above.
The said objective of the present invention is achieved by the following technique protocol.
The preparation of sodium alginate microshere vascular embolus containing gynecological drug consists of the following steps:
1. Gynecological drug solution is prepared by dissolving a certain rate of gynecological drug with solvent;
2. Sodium alginate solution is prepared by dissolving a certain rate of sodium alginate;
3. Curing solution is prepared by dissolving calcium chloride, barium chloride or magnesium chloride with the concentration of 1-10%;
4. Gynecological drug solution is mixed with sodium alginate solution, then the mixture is added dropwise to curing solution under a high-voltage electrostatic droplets device to form sodium alginate microspheres or microgel particles containing gynecological drug.
The high-voltage electrostatic droplets device comprises an electrostatic device, said electrostatic device has positive and negative electrodes. The positive electrode is connected with a needle of a micro-syringe device and the negative electrode is connected with a stainless steel wires emerged in the bivalent metal cationic curing solution. The mixture solution of gynecological drug and sodium alginate in the micro-syringe device is dripped into the bivalent cationic curing solution to form microspheres.
The obtained sodium alginate microshere vascular embolus containing gynecological drug is the microsphere reserving in the curing solution, which is called as wet-microsphere, the diameter can range from 200---550 m, 400^-750 m or 600950 m. Wet-microsphere of 300^-550 m is required for the treatment of adenomyosis, 500^750 m for uterine fibroids, and 700^950 m for the patients with demand of pregnancy.
The obtained sodium alginate microshere vascular embolus containing gynecological drug is decanted, then the lower microgel particles are put into the oven and kept in a sealed condition. The obtained powdery granules are called dry microspheres. The diameters of which may range from 100^-350 m, 200550 m or 400^750 m. Dry microsphere of 100^-350 m is required for the treatment of adenomyosis, 200^550 m for uterine fibroids, and 400--750 m for the patients with demand of pregnancy.
The third objective of the present invention is to provide application of the sodium alginate microshere vascular embolus containing gynecological drug mentioned above.
The said objective of the present invention is achieved by the following technique protocol.
By adopting intervention radiotherapy or intervention ultrasound, the duct is inserted into feeding artery of target organ to conduct arteriography. The selected diameter of embolus microsphere is determined according to the impression of arteriography. Aseptically open the bottle and leave it until the microspheres are settled at the bottom of the bottle. Remove the curing solution by a syringe then add an equal amount of normal saline to wash the microspheres three times, or remove the curing solution by a syringe then add an equal amount of normal saline, pour normal saline and microsphere into an aseptic bowl. Rinse the microsphere using 50-60 mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e.
embolism is finished. Arteriography is conducted again to judge the effect of embolism.
If the sodium alginate microshere vascular embolus containing gynecological drug is powdery granule, then the dry microsphere reserving in sealed container are dissolved in normal saline to swell (wet microsphere), then appropriate amount or diluted contrast medium is added to mix evenly (leaving microsphere thoroughly floating in the contrast medium), and then the mixture is infused slowly or slowly in multiple times in the vessel of the affected portion to embolism ultraselectively by duct under the monitor of image documentation equipment (Over-embolization is absolutely prohibited.) till the flow rate of contrast medium is obviously reduced, i.e. embolism is finished. Arteriography is conducted again to judge the effect of embolism.
The following is the further illustration of the present invention in embodiments, but it does not mean any limitation for the protection range of it.
Detailed Description of the Invention Example 1 Preparation of sodium alginate microsphere vascular embolus containing Danazol 1. Preparation before wrapping Disposal of glass utensil:
The clean glass utensil is dried then kept in oven at 300 C for 3 hours (the heat source is removed till the bacteria are killed);
(2) Preparation of Danazol solution:
1.5 kg Danazol available in market is weighed and placed in the glass utensil mentioned above, propylene glycol is added dropwise till Danazol is completely dissolved to make a Danazol solution;
Preparation of sodium alginate solution:
2.0 kg sodium alginate available in market is weighed and placed in the glass utensil, normal saline is added while stirring till sodium alginate is completely dissolved;
Preparation of 1% CaC12 solution;
The Danazol solution is mixed with sodium alginate solution;
The mixed solution is extracted by aseptic syringe and added into the calcium chloride solution under the high-voltage electrostatic droplet device.
The sodium alginate microsphere containing Danazol settles at the bottom of the glassware with diameter of 200-550 m.
The upper solution is decanted and the lower microgel particles are put into the oven and keeped in a sealed condition. The diameters of dry microspheres are 100^350 m. Prior to use, the dry microspheres should be rehydrated with normal saline for a couple of minutes.
Alternatively, the wet-microspheres can be used directly after the decanter of the upper solution and washed twice.
As for patients with myometrial gland, by adopting intervention radiotherapy or intervention ultrasound, insert the duct into feeding artery of target organ to conduct arteriography. Paclitaxel-containing sodium alginate microsphere with diameter ranging from 200-550 m is selected according to the impression of arteriography. Try to use micro-duct to carry out ultraselective embolus with aseptic operation. Extract CaCl2 solution from the bottle using injector and add in equal volume normal saline to rinse Danazol-containing sodium alginate microsphere (wet ball) for 3 times, or extract the described CaC12 solution from the bottle and add in equal volume normal saline, pour normal saline and microsphere into an aseptic bowl. Rinse the microsphere using 50-60 mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it into the foci slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e. embolism is finished. Arteriography is conducted again to judge the effect of embolism.
Example 2 Preparation of sodium alginate microsphere vascular embolus containing Gonadotropin releasing hormone analogues (GnRHa) 1. Preparation before wrapping Disposal of glass utensil:
The clean glass utensil is dried then kept in oven at 300 C for 3 hours (the heat source is removed till the bacteria are killed);
2 Preparation of Gonadotropin releasing hormone analogues (GnRHa) solution:
2 kg Gonadotropin releasing hormone analogues (GnRHa) available in market is weighed and placed in the glass utensil mentioned above, normal saline is added dropwise till Gonadotropin releasing hormone analogues (GnRHa) is completely dissolved to make a Gonadotropin releasing hormone analogues (GnRHa) solution;
Preparation of sodium alginate solution:
20 kg sodium alginate available in market is weighed and placed in the glass utensil, normal saline is added while stirring till sodium alginate is completely dissolved;
Preparation of 1 % MgC12 solution;
0 The Gonadotropin releasing hormone analogues (GnRHa) solution is mixed with sodium alginate solution;
The mixed solution is extracted by aseptic syringe and added into the MgCl2 solution under the high-voltage electrostatic droplet device. The sodium alginate microsphere containing Gonadotropin releasing hormone analogues (GnRHa) settles at the bottom of the glassware with diameter of 200^550 m.
The upper solution is decanted and the lower microgel particles are put into the oven and keeped in a sealed condition. The diameters of dry microspheres are s 100-350 m. Prior to use, the dry microspheres should be rehydrated with normal saline for a couple of minutes.
Alternatively, the wet-microspheres can be used directly after the decanter of the upper solution and washed twice.
As for patients with hysteromyoma, by adopting intervention radiotherapy or intervention ultrasound, insert the duct into feeding artery of target organ to conduct arteriography. Gonadotropin releasing hormone analogues (GnRHa)-containing sodium alginate microsphere with diameter ranging from 200-550 m is selected according to the impression of arteriography. Try to use micro-duct to carry out ultraselective embolus with aseptic operation. Extract CaC12 solution from the bottle using injector and add in equal volume normal saline to rinse paclitaxel-containing sodium alginate microsphere (wet ball) for 3 times, or extract the described MgCl2 solution from the bottle and add in equal volume normal saline, pour normal saline and microsphere into an aseptic bowl.
Rinse the microsphere using 50-60 mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it into the foci slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e. embolism is finished.
Arteriography is conducted again to judge the effect of embolism.
Example 3 Preparation of sodium alginate microsphere vascular embolus containing androgen 1. Preparation before wrapping ~i Disposal of glass utensil:
The clean glass utensil is dried then kept in oven at 300 C for 3 hours (the heat source is removed till the bacteria are killed);
2 Preparation of androgen solution:
2 kg androgen available in market is weighed and placed in the glass utensil mentioned above, acetone is added dropwise till androgen is completely dissolved;
0 Preparation of sodium alginate solution:
50kg sodium alginate available in market is weighed and placed in the glass utensil, normal saline is added while stirring till sodium alginate is completely dissolved;
Preparation of 6% BaC12 solution;
The androgen solution is mixed with sodium alginate solution;
The mixed solution is extracted by aseptic syringe and added into the BaC12 solution under the high-voltage electrostatic droplet device. The sodium alginate microspheres containing androgen settles at the bottom of the glassware with diameters of 600^950 m.
The upper solution is decanted and the lower microgel particles are put into the oven and kept in a sealed condition. The diameters of dry microspheres are 400-750 m. Prior to use, the dry microspheres should be rehydrated with normal saline for a couple of minutes.
Alternatively, the wet microspheres can be used directly after the decanter of the upper solution and washed twice.
As for patients with hysteromyoma, by adopting intervention radiotherapy or intervention ultrasound, insert the duct into feeding artery of target organ to conduct arteriography. androgen -containing sodium alginate microsphere with diameter ranging from 600-750 m is selected according to the impression of arteriography. Try to use ultraselective micro-duct to carry out embolus with II
aseptic operation while using. Extract CaC12 solution from the bottle using injector and add in equal volume normal saline to rinse androgen -containing sodium alginate microsphere (wet ball) for 3 times, or extract the described BaC12 solution from the bottle and add in equal volume normal saline, pour normal s saline and microsphere into an aseptic bowl. Rinse the microsphere using 50-mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it into the foci slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e. embolism is finished. Arteriography is conducted again to judge the effect of embolism.
Example 4 Preparation of sodium alginate microsphere vascular embolus containing gestrinone 1. Preparation before wrapping Disposal of glass utensil:
The clean glass utensil is dried then kept in oven at 300 C for 3 hours (the heat source is removed till the bacteria are killed);
0 Preparation of gestrinone solution:
2 kg androgen available in market is weighed and placed in the glass utensil mentioned above, propylene glycol is added dropwise till gestrinone is completely dissolved;
3 Preparation of sodium alginate solution:
150kg sodium alginate available in market is weighed and placed in the glass utensil, normal saline is added while stirring till sodium alginate is completely dissolved;
Preparation of 6% CaCl2 solution;
The gestrinone solution is mixed with sodium alginate solution;
The mixed solution is extracted by aseptic syringe and added into the calcium chloride solution under the high-voltage electrostatic droplet device.
The sodium alginate microspheres containing androgen settles at the bottom of the glassware with diameters of 500^'750 m.
The upper solution is decanted and the lower microgel particles are put into the oven and kept in a sealed condition. The diameters of dry microspheres are 300500 m. Prior to use, the dry microspheres should be rehydrated with normal saline for a couple of minutes.
Alternatively, the wet microspheres can be used directly after the decanter of the upper solution and washed twice.
As for patients with hysteromyoma, by adopting intervention radiotherapy or intervention ultrasound, insert the duct into feeding artery of target organ to conduct arteriography. gestrinone-containing sodium alginate microsphere with diameter ranging from 600-750 m is selected according to the impression of arteriography. Try to use ultraselective micro-duct to carry out embolus with aseptic operation while using. Extract CaC12 solution from the bottle using injector and add in equal volume normal saline to rinse androgen -containing sodium alginate microsphere (wet ball) for 3 times, or extract the described BaC12 solution from the bottle and add in equal volume normal saline, pour normal saline and microsphere into an aseptic bowl. Rinse the microsphere using 50-60 mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it into the foci slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e. embolism is finished. Arteriography is conducted again to judge the effect of embolism.
Example 5 Preparation of sodium alginate microsphere vascular embolus containing mifepristone 1. Preparation before wrapping D Disposal of glass utensil:
The clean glass utensil is dried then kept in oven at 300 C for 3 hours (the heat source is removed till the bacteria are killed);
(9 Preparation of mifepristone solution:
2 kg androgen available in market is weighed and placed in the glass utensil mentioned above, propylene glycol is added dropwise till gestrinone is completely dissolved;
3 Preparation of sodium alginate solution:
10kg sodium alginate available in market is weighed and placed in the glass utensil, normal saline is added while stirring till sodium alginate is completely dissolved;
Preparation of 6% MgCl2 solution;
The gestrinone solution is mixed with sodium alginate solution;
The mixed solution is extracted by aseptic syringe and added into the MgC12 solution under the high-voltage electrostatic droplet device. The sodium alginate microspheres containing androgen settles at the bottom of the glassware with diameters of 550700 m.
The upper solution is decanted and the lower microgel particles are put into the oven and kept in a sealed condition. The diameters of dry microspheres are 250^550 m. Prior to use, the dry microspheres should be rehydrated with normal saline for a couple of minutes.
Alternatively, the wet microspheres can be used directly after the decanter of the upper solution and washed twice.
As for patients with hysteromyoma, by adopting intervention radiotherapy or intervention ultrasound, insert the duct into feeding artery of target organ to conduct arteriography. mifepristone-containing sodium alginate microsphere with diameter ranging from 600-750 m is selected according to the impression of arteriography. Try to use ultraselective micro-duct to carry out embolus with aseptic operation while using. Extract CaC12 solution from the bottle using injector and add in equal volume normal saline to rinse androgen -containing sodium alginate microsphere (wet ball) for 3 times, or extract the described BaC12 solution from the bottle and add in equal volume normal saline, pour normal saline and microsphere into an aseptic bowl. Rinse the microsphere using 50-60 mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it into the foci slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e. embolism is finished. Arteriography is conducted again to judge the effect of embolism.
Industrial Application Sodium alginate, used as a drug carrier in this invention is natural extracts, which is a kind of polysaccharide sodium salt composed byp-D-mannitol and a-L-gulose extracted from natural brown algae. As a kind of linear macromolecule, its molecular weight is 50,000-100,000 Dalton. It has high hydrophilicity and can be easily dissolved in water forming viscous colloid.
Cross-link and solidification among macromolecular links may occur under the action of calcium ion. It can be processed into solid spherical or spherical like microsphere in different sizes according to clinical necessity. This kind of microsphere has good biocompatibility. In vivo the living organism, calcium ion may be gradually educed, and microsphere is nontoxicly degraded within 3-6 months due to molecular chain scission. No debris is produced during degradation, and it may also result in the eternal vascular embolism in target organs (When embolus remains in the vessel as long as 2 months, the intravascular thrombus may form and achieve the objective of eternal embolism.), thus to achieve the goal of treatment. In practical operation, using this kind of "biological multifunctional microsphere" embolism materials, by physical clogging tumor or arteriole vessel around the treated portion, may cause vascular closure, block blood supply and nutrients of the tissue in that portion, thus to induce atrophy and necrosis due to 1 ischemia and hypoxia. Meanwhile, it may provide advantageous condition for operation by reducing blood supply of target organs. Therefore, it shows dual therapeutic effect of embolism and drugs by taking this microsphere as drug carriers in treatment of gynecological diseases to slowly release to the tissue of local foci in a timing, positioning, and orientation way, thus to improve therapeutic efficacy greatly, especially for myometrial gland and hysteromyoma.
The sodium alginate microsphere vascular embolus containing gynecological drug for uterine artery embolization (UAE) are indicated for treating fibroids and adenomyosis by regional release of drug and interruption of blood supply.
The presented invention is charactered by the combination of gynecological drugs having direct therapeutic efficacy, such as Danazol, GnRHa, Mifepristone, Gestrinone, androgen, and sodium alginate(KMG), a biologically degradable drug-containing microsphere as an embolic agent for the treatment of fibroids and adenomyosis by means of intraarterial superselective embolization of uterine artery under radiological guidance is obtained. Release of the drugs lasts for about 2 months, leading to double therapeutic efficacy by regional medication and ischemia. Gradual release of the drugs could not only increase the regional drug concentration by first effect of drug but also reduce side-effect.
Meanwhile, some of the drugs released into the circulation system could provide long-term effect by accommodate the gonad axis.
2.0 kg sodium alginate available in market is weighed and placed in the glass utensil, normal saline is added while stirring till sodium alginate is completely dissolved;
Preparation of 1% CaC12 solution;
The Danazol solution is mixed with sodium alginate solution;
The mixed solution is extracted by aseptic syringe and added into the calcium chloride solution under the high-voltage electrostatic droplet device.
The sodium alginate microsphere containing Danazol settles at the bottom of the glassware with diameter of 200-550 m.
The upper solution is decanted and the lower microgel particles are put into the oven and keeped in a sealed condition. The diameters of dry microspheres are 100^350 m. Prior to use, the dry microspheres should be rehydrated with normal saline for a couple of minutes.
Alternatively, the wet-microspheres can be used directly after the decanter of the upper solution and washed twice.
As for patients with myometrial gland, by adopting intervention radiotherapy or intervention ultrasound, insert the duct into feeding artery of target organ to conduct arteriography. Paclitaxel-containing sodium alginate microsphere with diameter ranging from 200-550 m is selected according to the impression of arteriography. Try to use micro-duct to carry out ultraselective embolus with aseptic operation. Extract CaCl2 solution from the bottle using injector and add in equal volume normal saline to rinse Danazol-containing sodium alginate microsphere (wet ball) for 3 times, or extract the described CaC12 solution from the bottle and add in equal volume normal saline, pour normal saline and microsphere into an aseptic bowl. Rinse the microsphere using 50-60 mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it into the foci slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e. embolism is finished. Arteriography is conducted again to judge the effect of embolism.
Example 2 Preparation of sodium alginate microsphere vascular embolus containing Gonadotropin releasing hormone analogues (GnRHa) 1. Preparation before wrapping Disposal of glass utensil:
The clean glass utensil is dried then kept in oven at 300 C for 3 hours (the heat source is removed till the bacteria are killed);
2 Preparation of Gonadotropin releasing hormone analogues (GnRHa) solution:
2 kg Gonadotropin releasing hormone analogues (GnRHa) available in market is weighed and placed in the glass utensil mentioned above, normal saline is added dropwise till Gonadotropin releasing hormone analogues (GnRHa) is completely dissolved to make a Gonadotropin releasing hormone analogues (GnRHa) solution;
Preparation of sodium alginate solution:
20 kg sodium alginate available in market is weighed and placed in the glass utensil, normal saline is added while stirring till sodium alginate is completely dissolved;
Preparation of 1 % MgC12 solution;
0 The Gonadotropin releasing hormone analogues (GnRHa) solution is mixed with sodium alginate solution;
The mixed solution is extracted by aseptic syringe and added into the MgCl2 solution under the high-voltage electrostatic droplet device. The sodium alginate microsphere containing Gonadotropin releasing hormone analogues (GnRHa) settles at the bottom of the glassware with diameter of 200^550 m.
The upper solution is decanted and the lower microgel particles are put into the oven and keeped in a sealed condition. The diameters of dry microspheres are s 100-350 m. Prior to use, the dry microspheres should be rehydrated with normal saline for a couple of minutes.
Alternatively, the wet-microspheres can be used directly after the decanter of the upper solution and washed twice.
As for patients with hysteromyoma, by adopting intervention radiotherapy or intervention ultrasound, insert the duct into feeding artery of target organ to conduct arteriography. Gonadotropin releasing hormone analogues (GnRHa)-containing sodium alginate microsphere with diameter ranging from 200-550 m is selected according to the impression of arteriography. Try to use micro-duct to carry out ultraselective embolus with aseptic operation. Extract CaC12 solution from the bottle using injector and add in equal volume normal saline to rinse paclitaxel-containing sodium alginate microsphere (wet ball) for 3 times, or extract the described MgCl2 solution from the bottle and add in equal volume normal saline, pour normal saline and microsphere into an aseptic bowl.
Rinse the microsphere using 50-60 mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it into the foci slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e. embolism is finished.
Arteriography is conducted again to judge the effect of embolism.
Example 3 Preparation of sodium alginate microsphere vascular embolus containing androgen 1. Preparation before wrapping ~i Disposal of glass utensil:
The clean glass utensil is dried then kept in oven at 300 C for 3 hours (the heat source is removed till the bacteria are killed);
2 Preparation of androgen solution:
2 kg androgen available in market is weighed and placed in the glass utensil mentioned above, acetone is added dropwise till androgen is completely dissolved;
0 Preparation of sodium alginate solution:
50kg sodium alginate available in market is weighed and placed in the glass utensil, normal saline is added while stirring till sodium alginate is completely dissolved;
Preparation of 6% BaC12 solution;
The androgen solution is mixed with sodium alginate solution;
The mixed solution is extracted by aseptic syringe and added into the BaC12 solution under the high-voltage electrostatic droplet device. The sodium alginate microspheres containing androgen settles at the bottom of the glassware with diameters of 600^950 m.
The upper solution is decanted and the lower microgel particles are put into the oven and kept in a sealed condition. The diameters of dry microspheres are 400-750 m. Prior to use, the dry microspheres should be rehydrated with normal saline for a couple of minutes.
Alternatively, the wet microspheres can be used directly after the decanter of the upper solution and washed twice.
As for patients with hysteromyoma, by adopting intervention radiotherapy or intervention ultrasound, insert the duct into feeding artery of target organ to conduct arteriography. androgen -containing sodium alginate microsphere with diameter ranging from 600-750 m is selected according to the impression of arteriography. Try to use ultraselective micro-duct to carry out embolus with II
aseptic operation while using. Extract CaC12 solution from the bottle using injector and add in equal volume normal saline to rinse androgen -containing sodium alginate microsphere (wet ball) for 3 times, or extract the described BaC12 solution from the bottle and add in equal volume normal saline, pour normal s saline and microsphere into an aseptic bowl. Rinse the microsphere using 50-mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it into the foci slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e. embolism is finished. Arteriography is conducted again to judge the effect of embolism.
Example 4 Preparation of sodium alginate microsphere vascular embolus containing gestrinone 1. Preparation before wrapping Disposal of glass utensil:
The clean glass utensil is dried then kept in oven at 300 C for 3 hours (the heat source is removed till the bacteria are killed);
0 Preparation of gestrinone solution:
2 kg androgen available in market is weighed and placed in the glass utensil mentioned above, propylene glycol is added dropwise till gestrinone is completely dissolved;
3 Preparation of sodium alginate solution:
150kg sodium alginate available in market is weighed and placed in the glass utensil, normal saline is added while stirring till sodium alginate is completely dissolved;
Preparation of 6% CaCl2 solution;
The gestrinone solution is mixed with sodium alginate solution;
The mixed solution is extracted by aseptic syringe and added into the calcium chloride solution under the high-voltage electrostatic droplet device.
The sodium alginate microspheres containing androgen settles at the bottom of the glassware with diameters of 500^'750 m.
The upper solution is decanted and the lower microgel particles are put into the oven and kept in a sealed condition. The diameters of dry microspheres are 300500 m. Prior to use, the dry microspheres should be rehydrated with normal saline for a couple of minutes.
Alternatively, the wet microspheres can be used directly after the decanter of the upper solution and washed twice.
As for patients with hysteromyoma, by adopting intervention radiotherapy or intervention ultrasound, insert the duct into feeding artery of target organ to conduct arteriography. gestrinone-containing sodium alginate microsphere with diameter ranging from 600-750 m is selected according to the impression of arteriography. Try to use ultraselective micro-duct to carry out embolus with aseptic operation while using. Extract CaC12 solution from the bottle using injector and add in equal volume normal saline to rinse androgen -containing sodium alginate microsphere (wet ball) for 3 times, or extract the described BaC12 solution from the bottle and add in equal volume normal saline, pour normal saline and microsphere into an aseptic bowl. Rinse the microsphere using 50-60 mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it into the foci slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e. embolism is finished. Arteriography is conducted again to judge the effect of embolism.
Example 5 Preparation of sodium alginate microsphere vascular embolus containing mifepristone 1. Preparation before wrapping D Disposal of glass utensil:
The clean glass utensil is dried then kept in oven at 300 C for 3 hours (the heat source is removed till the bacteria are killed);
(9 Preparation of mifepristone solution:
2 kg androgen available in market is weighed and placed in the glass utensil mentioned above, propylene glycol is added dropwise till gestrinone is completely dissolved;
3 Preparation of sodium alginate solution:
10kg sodium alginate available in market is weighed and placed in the glass utensil, normal saline is added while stirring till sodium alginate is completely dissolved;
Preparation of 6% MgCl2 solution;
The gestrinone solution is mixed with sodium alginate solution;
The mixed solution is extracted by aseptic syringe and added into the MgC12 solution under the high-voltage electrostatic droplet device. The sodium alginate microspheres containing androgen settles at the bottom of the glassware with diameters of 550700 m.
The upper solution is decanted and the lower microgel particles are put into the oven and kept in a sealed condition. The diameters of dry microspheres are 250^550 m. Prior to use, the dry microspheres should be rehydrated with normal saline for a couple of minutes.
Alternatively, the wet microspheres can be used directly after the decanter of the upper solution and washed twice.
As for patients with hysteromyoma, by adopting intervention radiotherapy or intervention ultrasound, insert the duct into feeding artery of target organ to conduct arteriography. mifepristone-containing sodium alginate microsphere with diameter ranging from 600-750 m is selected according to the impression of arteriography. Try to use ultraselective micro-duct to carry out embolus with aseptic operation while using. Extract CaC12 solution from the bottle using injector and add in equal volume normal saline to rinse androgen -containing sodium alginate microsphere (wet ball) for 3 times, or extract the described BaC12 solution from the bottle and add in equal volume normal saline, pour normal saline and microsphere into an aseptic bowl. Rinse the microsphere using 50-60 mL normal saline once and discard the rinse solution, and then add in appropriate amount or diluted contrast medium to mix up evenly (leaving microsphere thoroughly floating in the contrast medium), and infuse it into the foci slowly or slowly in multiple times depending on concrete conditions by duct under fluoroscopy (Prohibit to overdose of embolism.) till flow rate of contrast medium is obviously reduced, i.e. embolism is finished. Arteriography is conducted again to judge the effect of embolism.
Industrial Application Sodium alginate, used as a drug carrier in this invention is natural extracts, which is a kind of polysaccharide sodium salt composed byp-D-mannitol and a-L-gulose extracted from natural brown algae. As a kind of linear macromolecule, its molecular weight is 50,000-100,000 Dalton. It has high hydrophilicity and can be easily dissolved in water forming viscous colloid.
Cross-link and solidification among macromolecular links may occur under the action of calcium ion. It can be processed into solid spherical or spherical like microsphere in different sizes according to clinical necessity. This kind of microsphere has good biocompatibility. In vivo the living organism, calcium ion may be gradually educed, and microsphere is nontoxicly degraded within 3-6 months due to molecular chain scission. No debris is produced during degradation, and it may also result in the eternal vascular embolism in target organs (When embolus remains in the vessel as long as 2 months, the intravascular thrombus may form and achieve the objective of eternal embolism.), thus to achieve the goal of treatment. In practical operation, using this kind of "biological multifunctional microsphere" embolism materials, by physical clogging tumor or arteriole vessel around the treated portion, may cause vascular closure, block blood supply and nutrients of the tissue in that portion, thus to induce atrophy and necrosis due to 1 ischemia and hypoxia. Meanwhile, it may provide advantageous condition for operation by reducing blood supply of target organs. Therefore, it shows dual therapeutic effect of embolism and drugs by taking this microsphere as drug carriers in treatment of gynecological diseases to slowly release to the tissue of local foci in a timing, positioning, and orientation way, thus to improve therapeutic efficacy greatly, especially for myometrial gland and hysteromyoma.
The sodium alginate microsphere vascular embolus containing gynecological drug for uterine artery embolization (UAE) are indicated for treating fibroids and adenomyosis by regional release of drug and interruption of blood supply.
The presented invention is charactered by the combination of gynecological drugs having direct therapeutic efficacy, such as Danazol, GnRHa, Mifepristone, Gestrinone, androgen, and sodium alginate(KMG), a biologically degradable drug-containing microsphere as an embolic agent for the treatment of fibroids and adenomyosis by means of intraarterial superselective embolization of uterine artery under radiological guidance is obtained. Release of the drugs lasts for about 2 months, leading to double therapeutic efficacy by regional medication and ischemia. Gradual release of the drugs could not only increase the regional drug concentration by first effect of drug but also reduce side-effect.
Meanwhile, some of the drugs released into the circulation system could provide long-term effect by accommodate the gonad axis.
Claims (13)
1. Sodium alginate microspheres containing a gynecological drug, wherein the microspheres comprise sodium alginate as a carrier, and said gynecological drug is enwrapped by said sodium alginate, and wherein said microspheres form a vascular embolus in a vein upon administration to a patient.
2. The sodium alginate microspheres of claim 1, wherein, the weight ratio of said sodium alginate and said gynecological drug ranges from 1:1 to 90:1.
3. The sodium alginate microspheres of claim 1, wherein said gynecological drug is an androgen compound.
4. The sodium alginate microspheres of claim 1, wherein said gynecological drug is gonadotropin releasing hormone or an analogue thereof.
5. The sodium alginate microspheres of claim 1, wherein said gynecological drug is Danazol, Mifepristone, or Gestrinone.
6. The sodium alginate microspheres of claim 1, wherein said sodium alginate microspheres comprise microgel particles or microspheres in solution.
7. The sodium alginate microspheres of claim 1, wherein said sodium alginate microspheres comprise powdery granules.
8. The sodium alginate microspheres of claim 6, wherein the diameter of the said microgel particles or microspheres ranges from 300-550µm or 500-750µm or 700-950µm.
9. The sodium alginate microspheres of claim 7, wherein, the diameter of the said powdery granules ranges from 100-350µm or 200-550µm or 400-750µm.
10. A method for the preparation of sodium alginate microspheres according to any one of claims 1 to 7, comprising the steps of:
(1) dissolving the gynecological drug with a first solvent to form a gynecological drug solution;
(2) dissolving the sodium alginate with a second solvent to form a sodium alginate solution;
(3) preparing a curing solution by dissolving calcium chloride, barium chloride or magnesium chloride into a third solvent at a concentration of 1-10 weight%; and (4) mixing the gynecological drug solution with the sodium alginate solution to produce a mixture, and adding the mixture dropwise to said curing solution under a high-voltage to form sodium alginate microspheres or microgel particles containing the gynecological drug, wherein steps (1), (2), and (3) are conducted simultaneously or sequentially in any order.
(1) dissolving the gynecological drug with a first solvent to form a gynecological drug solution;
(2) dissolving the sodium alginate with a second solvent to form a sodium alginate solution;
(3) preparing a curing solution by dissolving calcium chloride, barium chloride or magnesium chloride into a third solvent at a concentration of 1-10 weight%; and (4) mixing the gynecological drug solution with the sodium alginate solution to produce a mixture, and adding the mixture dropwise to said curing solution under a high-voltage to form sodium alginate microspheres or microgel particles containing the gynecological drug, wherein steps (1), (2), and (3) are conducted simultaneously or sequentially in any order.
11. The method of claim 10, wherein the high-voltage is generated by an electrostatic droplets device comprising an electrostatic device, said electrostatic device having positive and negative electrodes, the positive electrode being connected with a needle of a micro-syringe device and the negative electrode being connected with a stainless steel wire immersed in the curing solution, the mixture being dripped into the curing solution from the micro-syringe device to form microspheres.
12. The method of claim 10 or 11, further comprising the step of drying the sodium alginate microspheres to obtain powdery granules.
13. Use of the sodium alginate microspheres of any one of claims 1 to 7, in the treatment of a diseased tissue or organ, wherein the microspheres are to be placed into a vein of the diseased tissue or organ by way of a micro-catheter, so as to form a vascular embolus containing the gynecological drug in the vein.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2005/000506 WO2006108324A1 (en) | 2005-04-15 | 2005-04-15 | A gynecological pharmaceutics-containing microspherical vascular suppository of sodium alginate and its preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2602281A1 CA2602281A1 (en) | 2006-10-19 |
| CA2602281C true CA2602281C (en) | 2011-06-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2602281A Expired - Fee Related CA2602281C (en) | 2005-04-15 | 2005-04-15 | Gynecological drugs encapsulated in sodium alginate microspheres for use in embolotherapy |
Country Status (7)
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| US (1) | US20090028918A1 (en) |
| EP (1) | EP1870089A4 (en) |
| JP (1) | JP4937999B2 (en) |
| KR (1) | KR101163735B1 (en) |
| CA (1) | CA2602281C (en) |
| EA (1) | EA013680B1 (en) |
| WO (1) | WO2006108324A1 (en) |
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| CN101536986B (en) * | 2009-04-16 | 2011-05-04 | 北京圣医耀科技发展有限责任公司 | Sodium alginate targeted sustained release microsphere vascular occlusive agent containing Sorafenib as well as preparation and application thereof |
| CN102429862B (en) | 2011-11-29 | 2013-05-01 | 江苏德达医药科技有限公司 | Sustained-release povidone iodine eye drops |
| CN105362960A (en) * | 2015-12-18 | 2016-03-02 | 夏修菲 | Traditional Chinese medicine pill used for treating hysteromyoma and preparation method |
| KR102288833B1 (en) * | 2019-09-11 | 2021-08-13 | 주식회사 메피온 | Method for manufacturing self-expandable embolic material |
Family Cites Families (13)
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| JPH06329542A (en) * | 1993-05-21 | 1994-11-29 | Kibun Food Chemifa Co Ltd | Composition for local vascular hemostatis and composition for arterial chemical embolus containing insoluble aliginic acid salt particle |
| US5417982A (en) * | 1994-02-17 | 1995-05-23 | Modi; Pankaj | Controlled release of drugs or hormones in biodegradable polymer microspheres |
| JPH09165328A (en) * | 1995-12-15 | 1997-06-24 | Noboru Harada | Microsphere and composition for medicine containing the same |
| EP1263325B1 (en) * | 2000-03-06 | 2009-07-01 | Boston Scientific Limited | Embolic agents visible under ultrasound |
| CN1106845C (en) * | 2000-08-17 | 2003-04-30 | 洪宏 | Process for preparing solid-state-microspherical vascular suppository of sodium alginate |
| US7008633B2 (en) * | 2000-12-18 | 2006-03-07 | Board Of Regents, The University Of Texas System | Local regional chemotherapy and radiotherapy using in situ hydrogel |
| US6749845B2 (en) * | 2001-02-15 | 2004-06-15 | Aeropharm Technology, Inc. | Modulated release particles for lung delivery |
| US7462366B2 (en) * | 2002-03-29 | 2008-12-09 | Boston Scientific Scimed, Inc. | Drug delivery particle |
| US20040076582A1 (en) * | 2002-08-30 | 2004-04-22 | Dimatteo Kristian | Agent delivery particle |
| CN1476897A (en) * | 2002-08-21 | 2004-02-25 | 中国科学院大连化学物理研究所 | Preparation technique of protein medicine microsphere carrier with small grain size |
| WO2005041884A2 (en) * | 2003-10-31 | 2005-05-12 | Engineered Release Systems, Inc | Polymer-based microstructures |
| CN1319525C (en) * | 2004-09-16 | 2007-06-06 | 北京圣医耀科技发展有限责任公司 | Taxinol-sodium alginate micro ball vascular embolism agent and its preparation |
| US20080160062A1 (en) * | 2006-12-29 | 2008-07-03 | Boston Scientific Scimed, Inc. | Medical devices based on modified polyols |
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2005
- 2005-04-15 KR KR1020077025300A patent/KR101163735B1/en active IP Right Grant
- 2005-04-15 JP JP2008505713A patent/JP4937999B2/en not_active Expired - Fee Related
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- 2005-04-15 WO PCT/CN2005/000506 patent/WO2006108324A1/en active Application Filing
- 2005-04-15 CA CA2602281A patent/CA2602281C/en not_active Expired - Fee Related
- 2005-04-15 EA EA200702256A patent/EA013680B1/en not_active IP Right Cessation
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Also Published As
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|---|---|
| CA2602281A1 (en) | 2006-10-19 |
| KR20080009703A (en) | 2008-01-29 |
| US20090028918A1 (en) | 2009-01-29 |
| EA013680B1 (en) | 2010-06-30 |
| JP4937999B2 (en) | 2012-05-23 |
| EP1870089A4 (en) | 2012-10-03 |
| EA200702256A1 (en) | 2008-04-28 |
| EP1870089A1 (en) | 2007-12-26 |
| WO2006108324A1 (en) | 2006-10-19 |
| KR101163735B1 (en) | 2012-07-09 |
| JP2008535870A (en) | 2008-09-04 |
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